Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
10.4.1.3 Cell Division Arrest
In some circumstances it may be useful to eliminate a target cell's ability to replicate via cell division, thus rendering it incapable of further growth. For example, many prokaryotic microorganisms respond to starvation by entering growth-free stationary phases3710-3712 or by forming dormant spores;2116 nanorobot manipulation of cellular biochemical states possibly could induce stasis in bacteria, though spore formation should be avoided. The Bcl-2 protein family can modulate eukaryotic cell cycle progression; under suboptimal growth conditions, Bcl-2 promotes exit into quiescence and retards reentry into cycle.2097 A gene fragment on human chromosome 4, called mortality factor 4 (morf4), when added to cancerous (eukaryotic) cells in vitro converts proliferating cells into senescent cells that have stopped dividing.2128 Ceramide, the breakdown product of sphingomyelins, can drive a eukaryotic cell either to cycle arrest, or to apoptosis, depending upon other conditions within the cell,2062 and p16 and p27 are known eukaryotic cell cycle inhibitors.2059 Cytochalasins, which are derived from molds, interfere with the division of cytoplasm, inhibit cell movement, and can cause extrusion of the interphase nucleus.3718
Eukaryotic mitosis has four distinct stages (prophase, metaphase, anaphase, telophase) and interphase (between divisions), each associated with distinct biochemical and cytoarchitectural states. Thus it is not surprising that specific biochemical agents have been found that are capable of selectively halting, accelerating, or altering mitosis at any of the many stages; a few examples are in Table 10.4. Cell cycle control is discussed further in Chapter 12.
Many chemotherapeutic agents function by eliminating the cell's ability to undergo mitosis. For example, plicamycin (mithramycin) is believed to form a complex with DNA which inhibits DNA-dependent or DNA-directed cellular RNA and enzymatic RNA synthesis -- 48-hour lethal dose in human HeLa cancer cells is ~1 part/million by weight or ~105 molecules/cell.2119 Eukaryotic cell cycling may be interrupted by inhibitors of RNA polymerases I, II, and III (which produce RNAs specific to different functions in the cell), or by inhibitors of uracil synthesis or other steps in general RNA base production which would interfere with RNA synthesis overall. Vincristine applied at similar dosage (e.g., ~10-18 kg/cell) inhibits microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.2119 Large doses lead to necrotic cytocide; a smaller dose may trigger apoptosis.
A theoretical enzyme capable of selectively lysing DNA telomeres in the nucleus would prevent cell replication, but would probably trigger apoptosis due to massive chromatin damage because TTAGGG sequences are scattered throughout the chromosome.383 Telomere length affects eukaryotic cell division only indirectly, either because short telomeres activate a DNA damage response that blocks cell division or because genes near the ends of chromosomes which are essential for cell division may be lost or misregulated. Telomerolytic enzymes would be useless against common bacteria (e.g., E. coli) and viruses (e.g., SV40) which have circular DNA chromosomes, or viruses such as the adenoviruses that cause bronchitis and pneumonia which have linear DNA locked with a terminal protein -- but no telomeres in either case.383 Alternatively, R. Bradbury suggests the introduction of DNA (or RNA) for antisense sequences, for genes essential for cell cycle progression or for proteases which cut or digest these same proteins, as for instance an antisense gene for cyclin or one of the many cdc genes -- if phosphorylation or dephosphorylation of the cyclins or cdc genes is occurring, the introduction of a phosphatase or kinase could easily block the entire cell division process.
Last updated on 24 February 2003